Analysis of onset mechanisms of a sphingosine 1-phosphate receptor modulator fingolomod-induced atrioventricular conduction block

• Project/Area Number: 25460344
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Toho University
• Principal Investigator: SUGIYAMA Atsushi 東邦大学, 医学部, 教授 (60242632)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: スフィンゴシン1-リン酸 / フィンゴリモド / 房室伝導ブロック / Giタンパク / スフィンゴシン1-リン / fingolimod / 房室結節ブロック / 房室ブロック

Outline of Final Research Achievements

Since a sphingosine 1-phosphate receptor modulator fingolimod induced complete atrioventricular conduction block, onset mechanisms of fingolomod-induced atrioventricular conduction block were analyzed. Fingolimod suppressed adenylate cyclase activity of the membrane preparation made of atrioventricular nodal tissue of guinea-pig hearts, suggesting that fingolomod may stimulate Gi protein in the atrioventricular node. Thus, S1P receptor subtype 1 in the atrioventricular node could be one of the candidates for fingolimod-induced atrioventricular conduction block.

Research Products

• [Journal Article] Why can dl-sotalol prolong the QT Interval in vivo despite its weak inhibitory effect on hERG K+ channels in vitro? : electrophysiological and pharmacokinetic analysis with the halothane-anesthetized guinea-pig model (2016)
  • Author(s): Katagi J, Nakamura Y, Cao X, Ohara H, Honda A, Izumi-Nakaseko H, Ando K, Sugiyama A
  • Journal Title: Cardiovasc Toxicol Volume: 16 Issue: 2 Pages: 138-146
  • DOI: 10.1007/s12012-015-9322-2
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Antiviral drug vidarabine possessing cardiac type 5 adenylyl cyclase inhibitory property did not affect cardiohemodynamic or electrophysiological variables in the halothane-anesthetized dogs (2016)
  • Author(s): Wada T, Nakamura Y, Cao X, Ohara H, Izumi-Nakaseko H, Ando K, Nakazato Y, Sugiyama A
  • Journal Title: The Journal of Toxicological Sciences Volume: 41 Issue: 1 Pages: 115-122
  • DOI: 10.2131/jts.41.115
  • NAID: 130005119778
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Feasible induction of coronary artery vasospasm occurred during cardiac catheterization in a microminipig (2016)
  • Author(s): Matsukura S, Nakamura Y, Ohara H, Cao X, Wada T, Izumi-Nakaseko H, Ando K, Akasaka Y, Sugiyama A
  • Journal Title: J Vet Med Sci Volume: 78 Pages: 873-876
  • NAID: 130005154307
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of a prostagrandin EP4-receptor agonist ONO-AE1-329 on the left ventricular pressure-volume relationship in the halothane-anesthetized dogs (2016)
  • Author(s): Honda A, Nakamura Y, Ohara H, Cao X, Nomura H, Katagi J, Wada T, Izumi-Nakaseko H, Ando K, Sugiyama A
  • Journal Title: Eur J Pharmacol Volume: 775 Pages: 130-137
  • DOI: 10.1016/j.ejphar.2016.02.029
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Electropharmacological effects of amantadine on cardiovascular system assessed with J-Tpeak and Tpeak-Tend analysis in the halothane-anesthetized beagle dogs (2016)
  • Author(s): Cao X, Nakamura Y, Wada T, Izumi-Nakaseko H, Ando K, Sugiyama A
  • Journal Title: J Toxicol Sci Volume: 41 Pages: 439-447
  • NAID: 130005152342
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Intravenous administration of apomorphine does not induce long QT syndrome: experimental evidence from in vivo canine models (2015)
  • Author(s): Watanabe Y, Nakamura Y, Cao X, Ohara H, Yamazaki Y, Murayama N, Sugiyama Y, Izumi-Nakaseko H, Ando K, Yamazaki H, Sugiyama A
  • Journal Title: Basic Clin Pharmacol Toxicol Volume: 116 Issue: 6 Pages: 468-475
  • DOI: 10.1111/bcpt.12343
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO-AE1-329 in the halothane-anesthetized dogs (2015)
  • Author(s): Nomura H, Nakamura Y, Cao X, Honda A, Katagi J, Ohara H, Izumi-Nakaseko H, Satoh Y, Ando K, Sugiyama A
  • Journal Title: Eur J Pharmacol Volume: 761 Pages: 217-225
  • DOI: 10.1016/j.ejphar.2015.06.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fluvoxamine by itself has potential to directly induce long QT syndrome at supra-therapeutic concentrations. (2015)
  • Author(s): Yamazaki-Hashimoto Y, Nakamura Y, Ohara H, Cao X, Kitahara K, Izumi-Nakaseko H, Ando K, Yamazaki H, Ikeda T, Yamazaki J, Sugiyama A
  • Journal Title: The Journal of Toxicological Sciences Volume: 40 Issue: 1 Pages: 33-42
  • DOI: 10.2131/jts.40.33
  • NAID: 130004904019
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of selective IKr channel blockade by E-4031 on ventricular electro-mechanical relationship in the halothane-anesthetized dogs. (2014)
  • Author(s): Izumi-Nakaseko H, Nakamura Y, Cao X, Ohara H, Yamazaki Y, Ueda N, Ando K, Sugiyama A
  • Journal Title: European Journal of Pharmacology Volume: 740 Pages: 263-270
  • DOI: 10.1016/j.ejphar.2014.06.064
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Analysis of onset mechanisms of a sphingosine 1-phosphate receptor modulator fingolimod-induced atrioventricular conduction block and QT-interval prolongation. (2014)
  • Author(s): Yagi Y, Nakamura Y, Kitahara K, Harada T, Kato K, Ninomiya T, Cao X, Ohara H, Izumi-Nakaseko H, Suzuki K, Ando K, Sugiyama A
  • Journal Title: Toxicology and applied pharmacology Volume: 16 Issue: 1 Pages: 39-47
  • DOI: 10.1016/j.taap.2014.09.006
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effects of pH on Nifekalant-Induced Electrophysiological Change Assessed in the Langendorff Heart Model of Guinea Pigs (2014)
  • Author(s): Kazuyuki Kazusa, Yuji Nakamura, Yudai Watanabe, Kentaro Ando, Atsushi Sugiyama
  • Journal Title: Journal of Pharmacological Sciences Volume: 124 Issue: 2 Pages: 153-159
  • DOI: 10.1254/jphs.13127FP
  • NAID: 130003391474
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Assessment of Testing Methods for Drug-Induced Repolarization Delay and Arrhythmias in an iPS Cell–Derived Cardiomyocyte Sheet: Multi-site Validation Study (2014)
  • Author(s): Nakamura Y., Matsuo J., Miyamoto N., Ojima A., Ando K., Kanda Y., Sawada K., Sugiyama A., Sekino Y.
  • Journal Title: Journal of Pharmacological Sciences Volume: 124 Issue: 4 Pages: 494-501
  • DOI: 10.1254/jphs.13248FP
  • NAID: 130003391508
  • ISSN: 1347-8613, 1347-8648
  • Peer Reviewed
• [Journal Article] Electrophysiological effects of an anti-influenza drug oseltamivir on the guinea-pig atrium: comparison with those of pilsicainide (2013)
  • Author(s): Akira Takahara, Sanae Suzuki, Mihoko Hagiwara, Shuhei Nozaki, Atsushi Sugiyama
  • Journal Title: Biological & pharmaceutical bulletin Volume: 36 Pages: 1650-1652
  • NAID: 130004147313
  • Peer Reviewed
• [Presentation] Current situation and future plan in Japanese activity of Kirishima Meeting (2015)
  • Author(s): Atsushi Sugiyama
  • Organizer: Safety Pharmacology Society, 15th annual meeting
  • Place of Presentation: プラハ、チェコ共和国
  • Year and Date: 2015-10-01
  • Int'l Joint Research / Invited
• [Presentation] 薬物性不整脈 (2015)
  • Author(s): 杉山篤
  • Organizer: 第51回日本小児循環器学会総会・学術集会
  • Place of Presentation: ホテル日航東京（東京都港区）
  • Year and Date: 2015-07-18
  • Invited
• [Presentation] The current trends and issues on integrated cardiac safety. (2014)
  • Author(s): Sugiyama A
  • Organizer: The 5th DIA cardiac safety workshop in Japan
  • Place of Presentation: KFCホール両国（東京都・墨田区）
  • Year and Date: 2014-10-23
  • Invited
• [Presentation] Overview and raising issues. (2014)
  • Author(s): Sugiyama A
  • Organizer: The 5th DIA cardiac safety workshop in Japan
  • Place of Presentation: KFCホール両国（東京都・墨田区）
  • Year and Date: 2014-10-23
  • Invited
• [Presentation] 心房に対するオセルタミビルの電気生理学的作用：モルモット単離心房標本による検討
  • Author(s): 萩原 美帆子, 鈴木 早苗, 野崎 修平, 杉山 篤, 高原 章
  • Organizer: 第128回日本薬理学会関東部会
  • Place of Presentation: 早稲田大学国際会議場、新宿区、東京都
• [Presentation] Aminodaroneおよびdronedaroneの心房・心室有効不応期に対する作用：bepridilおよびdl-sotalolとの比較
  • Author(s): 小原 浩, 中村裕二, 本川佳幸, 山﨑有希子, 曹 新, 安東賢太郎, 池田隆徳, 杉山 篤
  • Organizer: 第18回アミオダロン研究会
  • Place of Presentation: 経団連ホール、千代田区、東京都
• [Presentation] Azithromycinの血行動態および電気生理学的作用：ハロセン麻酔犬モデルでの評価
  • Author(s): 小原 浩, 中村裕二, 安東賢太郎, 渡辺雄大, 曹 新, 山﨑有希子, 池田隆徳, 杉山 篤
  • Organizer: 第30回日本心電学会学術集会
  • Place of Presentation: リンクステーションホール青森、青森市、青森県
• [Presentation] Assessment of Testing Methods of the Drug-Induced Repolarization Delay and Arrythmias in an iPS-Derived Cardiomyocyte Sheet:Multi-Site Validation Study
  • Author(s): 中村裕二, 松尾純子, 宮本憲優, 小島敦子, 安東賢太郎, 諫田泰成, 澤田光平, 杉山 篤, 関野祐子
  • Organizer: 第5回日本安全性薬理研究会 学術年会
  • Place of Presentation: 東京大学、文京区、東京都
• [Presentation] 不整脈心電図の読み方
  • Author(s): 杉山 篤
  • Organizer: 第5回安全性薬理研究会 学術年会
  • Place of Presentation: 東京大学、文京区、東京都
  • Invited
• [Presentation] Effects of Selective Ikr Channel Blockade by E-4031 on Ventricular Electro-Mechanical Relationship in the Halothane-Anesthetized Dogs
  • Author(s): 中瀬古寛子, 中村裕二, 曹 新, 小原 浩 ,山崎有希子, 上田直也, 安東賢太郎, 杉山 篤
  • Organizer: 第5回安全性薬理研究会 学術年会
  • Place of Presentation: 東京大学、文京区、東京都
• [Presentation] 腎交感神経除去術の慢性房室ブロック犬の心血管系に対する作用：シルニジピンおよびアミオダロンとの比較
  • Author(s): 小原 浩, 中村裕二, 曹 新, 横山浩史, 中瀬古寛子, 安東賢太郎, 村越伸行, 佐藤明, 青沼和隆, 高原章, 池田隆徳, 杉山 篤
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター、仙台市、宮城県
• [Presentation] アマンタジンの電気薬理学的作用：ハロセン麻酔犬モデルでの評価
  • Author(s): 曹 新, 中村裕二, 小原 浩, 山﨑有希子, 中瀬古寛子, 安東賢太郎, 杉山 篤
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター、仙台市、宮城県
• [Presentation] E-4031の電気生理学的特徴および催不整脈作用の評価：ハロセン麻酔および慢性房室ブロック犬モデルでの検討
  • Author(s): 中瀬古（泉）寛子, 中村 裕二, 曹 新, 上田直也, 小原 浩, 山崎有希子, 安東賢太郎, 杉山 篤
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター、仙台市、宮城県
• [Presentation] オセルタミビルは高頻度刺激により誘発された心房細動を抑制する：ラット動静脈瘻心拡大モデルを用いた検討
  • Author(s): 灘 みづき, 相本 恵美, 八木 啓太, 江沢 亜耶, 杉山 篤, 高原 章
  • Organizer: 第87回日本薬理学会年会
  • Place of Presentation: 仙台国際センター、仙台市、宮城県
• [Book] 動物の心電図・心エコー・血圧・病理学検査 増補改訂版 (2013)
  • Author(s): 杉山 篤, 中村裕二
  • Publisher: 丸善出版
• [Remarks] 東邦大学 教育・研究業績データベース
  • URL: http://gyoseki.toho-u.ac.jp/thuhp/KgApp?kozac=22002900&year=2015